The prior art recognizes that peptide transport permease systems are one mechanism by which chemical substances are carried through the cell membrane of an antimicrobial organism. Both di- and oligopeptide transport systems are present in the cell membrane, for example, in the cell membrane of Escherichia coli, B. C. Ames, Proc. Nat. Acad. Sci. OSH 70 456 (1973), C. Gilvarg, Nature, the New Biology 241 161 (1973).
Peptide transport systems are widespread in both procaryotic and eukaryotic microorganisms. A prodrug which can be transported per se through the cell membrane of such organisms via the permease system and, then, release the drug within the cell would possess enhanced activity.
A number of synthetic derivatives have been prepared which take advantage of these transport systems such as those described by M. M. Ponpipom, et al., J. Med. Chem. 24 1388 (1981), European Patent Office application No. 38,541 or C. Philip et al., PCT application, publication No. WO81/01145. Some of these types of compounds were designed to limit toxicity or to achieve more specific biological activity. Most compounds of the prior art are active, without degradation at the receptor site, in the transport form due to their resistance to intracellular peptidases. In other words, they are not in latentiated form as are the compounds of this invention. For example, the Philip publication, cited above, discloses anti-tumor moieties which are attached by a covalent bond to a polypeptide.
A number of potentially useful chemotherapeutic agents are present in the prior art which are impermeant or poorly permeant to the cell membrane of an infecting organism. The impermeant nature of these compounds may be due to the inherent physico-chemical properties of the compounds or due to an acquired resistance to them in the permease system of the cell membrane of the target species.
Several related United States patents describe compounds which have angiotensin converting enzyme inhibiting activity whose structures have a tripeptide containing a central cysteinyl unit attached to a proline-like ring by means of a disulfide bond, U.S. Pat. Nos. 4,284,624; 4,325,943; 4,325,944 and 4,325,945.
Another series of U.S. patents, U.S. Pat. Nos. 4,237,267 and 4,258,193, disclose a large number of disulfides which are used in exchange reactions, including a few compounds with structures having pyridine N-oxide attached via a disulfide bond to the alanyl unit of an oligopeptide or to alanine itself.
The S-ethylthio protective group has been used, along with others, in procedures to prepare cysteine-containing peptides. The S-ethylthio group was inserted into the peptide structures by displacement of an S-guanylthio moiety by ethylmercaptan in a solvent system of dimethylformamide-triethylamine, H. Kunzek et al., J. Prakt. Chemie, 322 186 (1980).
J. V. Castell et al., Helv. 62 2507 (1979), reported that a mixed cysteine-pyridine disulfide reacted, by displacement, with various mercaptans in acetic acid to form mixed disulfides during a study of the use of 2-pyridine sulfenyl chloride to form protected cysteinyl derivatives.